Comparison of DNA adduct levels associated with oxidative stress in human pancreas
Comparison of DNA adduct levels associated with oxidative stress in human pancreas
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DOI：
10.1016/s0027-5107(98)00129-8
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发表时间：
1998-09-20
影响因子：
2.3
通讯作者：
Bartsch, H
中科院分区：
文献类型：
--
作者：
Kadlubar, FF;Anderson, KE;Bartsch, H
与氧化应激相关的DNA加合物被认为涉及由氧化损伤和脂质过氧化产生的内源性反应物质的形成。尽管不同的实验室报告了几种人体组织中的这些加合物，但尚未对相同组织样本中这些加合物的水平进行比较。在这项研究中，我们从15名吸烟者和15名非吸烟者的胰腺中分离DNA，并测量1，N-6-乙烯基（2 '-脱氧）鸟苷（edA），3，N-4-乙烯基（2'-脱氧）胞苷（edC），8-氧代-2 '-脱氧鸟苷（8-oxo-dG）和嘧啶并[1，2-alpha]嘌呤-10（3 H）-酮（m（1）G）的水平。使用相同的DNA，确定谷胱甘肽S-转移酶（GST）MI、GSTT 1和NAD（P）H醌还原酶-1（NQO（1））基因型，以评估其基因产物通过分别参与脂质过氧化产物的解毒和氧化还原循环在调节加合物水平中的作用。观察到的最高加合物水平是m（1）G，其次是8-oxo-dG，edA和edC，但吸烟者和非吸烟者之间的加合物水平没有差异，与受试者的年龄，性别或体重指数无关。此外，edA和eC之间，或edA或edC与m（1）G或8-oxo-dG之间的加合物水平没有相关性。然而，在人胰腺DNA中8-oxo-dG和m（1）G的水平之间存在显著的相关性（r = 0.76; p < 0.01）。GSTM 1和NQO（1）基因型均与任何加合物水平的差异无关。尽管样本集有限，但数据表明，人类胰腺中内源性DNA加合物的形成并不明显来自吸烟或（NQO（1））介导的氧化还原循环。此外，似乎GSTM 1和GSTT 1都不能明显地防止内源性加合物的形成。加上m（1）G和edA或edC之间缺乏相关性，这些数据表明，脂质过氧化产生的丙二醛可能不会显着促进m（1）G加合物的形成。另一方面，m（1）G和8-oxo-dG之间的明显相关性以及它们相当高的水平与以下假设一致：m（1）G主要通过DNA与碱基丙烯醛反应形成，而碱基丙烯醛与8-oxo-dG一样，被认为是由羟基自由基攻击DNA而产生的。(C)1998 Elsevier Science B. V.保留所有权利。
DNA adducts associated with oxidative stress are believed to involve the formation of endogenous reactive species generated by oxidative damage and lipid peroxidation. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been carried out. In this study, we isolated DNA from the pancreas of 15 smokers and 15 non-smokers, and measured the levels of 1,N-6-etheno(2'-deoxy)guanosine (edA), 3,N-4-etheno(2'-deoxy)cytidine (edC), 8-oxo-2'-deoxyguanosine (8-oxo-dG), and pyrimido[1,2-alpha]purin-10(3H)-one (m(1)G). Using the same DNA, the glutathione S-transferase (GST) MI, GSTT1, and NAD(P)H quinone reductase-l (NQO(1)) genotypes were determined in order to assess the role of their gene products in modulating adduct levels through their involvement in detoxification of lipid peroxidation products and redox cycling, respectively. The highest adduct levels observed were for m(1)G, followed by 8-oxo-dG, edA, and edC, but there were no differences in adduct levels between smokers and non-smokers and no correlation with the age, sex or body mass index of the subject. Moreover, there was no correlation in adduct levels between edA and eC, or between edA or edC and m(1)G or 8-oxo-dG. However, there was a significant correlation (r = 0.76; p < 0.01) between the levels of 8-oxo-dG and m(1)G in human pancreas DNA. Neither GSTM1 nor NQO(1) genotypes were associated with differences in any of the adduct levels. Although the sample set was Limited, the data suggest that endogenous DNA adduct formation in human pancreas is not clearly derived from cigarette smoking or from (NQO(1))-mediated redox cycling. Further, it appears that neither GSTM1 nor GSTT1 appreciably protects against endogenous adduct formation. Together with the lack of correlation between m(1)G and edA or edC, these data indicate that the malondialdehyde derived from lipid peroxidation may not contribute significantly to m(1)G adduct formation. On the other hand, the apparent correlation between m(1)G and 8-oxo-dG and their comparable high levels are consistent with the hypothesis that m(1)G is formed primarily by reaction of DNA with a base propenal, which, like 8-oxo-dG, is thought to be derived from hydroxyl radical attack on the DNA. (C) 1998 Elsevier Science B.V. All rights reserved.